CN102276520B - Process for the preparation of a 2-ethylaminopyridine derivative - Google Patents
Process for the preparation of a 2-ethylaminopyridine derivative Download PDFInfo
- Publication number
- CN102276520B CN102276520B CN201110165787.3A CN201110165787A CN102276520B CN 102276520 B CN102276520 B CN 102276520B CN 201110165787 A CN201110165787 A CN 201110165787A CN 102276520 B CN102276520 B CN 102276520B
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- China
- Prior art keywords
- halogen atom
- alkyl
- general formula
- haloalkyl
- pyridine
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 42
- CXGFWBPQQXZELI-UHFFFAOYSA-N n-ethylpyridin-2-amine Chemical class CCNC1=CC=CC=N1 CXGFWBPQQXZELI-UHFFFAOYSA-N 0.000 title abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims description 169
- -1 alkyl cyanoacetates Chemical class 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 19
- 239000003513 alkali Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 150000003857 carboxamides Chemical class 0.000 claims description 3
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910003445 palladium oxide Inorganic materials 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229960001866 silicon dioxide Drugs 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 claims 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 1
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 claims 1
- BSAQKHKYJMRZFK-UHFFFAOYSA-N n-(2-pyridin-2-ylethyl)formamide Chemical class O=CNCCC1=CC=CC=N1 BSAQKHKYJMRZFK-UHFFFAOYSA-N 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 36
- 125000000623 heterocyclic group Chemical group 0.000 description 34
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- UBKKNWJGYLSDSJ-UHFFFAOYSA-N 2-methylpyridine-3-carbonitrile Chemical class CC1=NC=CC=C1C#N UBKKNWJGYLSDSJ-UHFFFAOYSA-N 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000004448 titration Methods 0.000 description 6
- 0 CCC1=NC=C*(CC*(C)=C)C=C1 Chemical compound CCC1=NC=C*(CC*(C)=C)C=C1 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003905 agrochemical Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 2
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical compound C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- RRNXYHYDSDAOFW-UHFFFAOYSA-N 2,3-bis(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CN=C1C(F)(F)F RRNXYHYDSDAOFW-UHFFFAOYSA-N 0.000 description 1
- MXIUWSYTQJLIKE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1C(Cl)=O MXIUWSYTQJLIKE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
- 125000006331 halo benzoyl group Chemical group 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940031815 mycocide Drugs 0.000 description 1
- ZCAKTXBGIROUFM-UHFFFAOYSA-N n,n-dimethyl-1-phenylmethanamine;pyridine Chemical compound C1=CC=NC=C1.CN(C)CC1=CC=CC=C1 ZCAKTXBGIROUFM-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical group 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 1
- BFNYNEMRWHFIMR-UHFFFAOYSA-N tert-butyl 2-cyanoacetate Chemical compound CC(C)(C)OC(=O)CC#N BFNYNEMRWHFIMR-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for the preparation of a 2-ethylaminopyridine derivative of general formula (I) or a salt thereof is disclosed. A process for the preparation of a N-[2-(2-pyridinyl)ethyl]carboxamide derivative of general formula (II) or a salt thereof Intermediate of general formula (III) is disclosed.
Description
Patent application of the present invention is that international application no is PCT/EP2005/056900, international filing date is on December 19th, 2005, the application number that enters the China national stage is " 200580043558.7 ", and denomination of invention is the divisional application of the application for a patent for invention of " preparation method of 2-ethylamino pyridine derivate ".
The present invention relates to a kind of novel method of being prepared 2-ethylamino pyridine derivate by 2-haloperidid derivative, this 2-ethylamino pyridine derivate can be used as preparing the intermediate compound of agricultural chemicals.
Patent application WO 2004/016088 has disclosed N-[2-(2-pyridyl) ethyl] preparation of benzamide derivatives, first produce 2-ethylamino pyridine derivate, then these 2-ethylamino pyridine derivates and the coupling of halo benzoyl derivative by 2-haloperidid derivative.The step of the method comprise 2-methyl cyanopyridine derivative under metal catalyst exists, in protonic solvent, be reduced to 2-ethylamino pyridine.
The shortcoming of the method disclosing in this patent application is that the productive rate of 2-methyl cyanopyridine derivative reduction generation 2-ethylamino pyridine derivate step is lower, is difficult to accept in technical scale.
Another shortcoming of the method disclosing in this patent application is must carry out two independent steps to prepare 2-methyl cyanopyridine derivative by 2-haloperidid derivative.This causes increasing the cost of method, and the overall yield of reduction method is difficult to accept in technical scale.
The inventor has been found that the another kind of method of preparation 2-ethylamino pyridine derivate, and the method has overcome these problems, and can be used for industrial-scale operation.
Therefore, the present invention relates to one prepare the 2-ethylamino pyridine derivate of general formula (I) or its salt with and the method for the N-oxide compound of 2-pyridine
In formula:
-p equals 1,2,3 or 4 integer;
-X is identical or different, and is hydrogen atom, halogen atom, nitro, cyano group, hydroxyl, amino, sulfanyl (sulfanyl), five fluoro-λ
6-sulfanyl, formyl radical, methanoyl, formamido group, carboxyl, formamyl, N-hydroxyl amino formyl radical, carbamate groups, (oximido)-C
1-C
6-alkyl, C
1-C
8-alkyl, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
8-alkylamino, two-C
1-C
8-alkylamino, C
1-C
8-alkoxyl group, there is the C of 1 to 5 halogen atom
1-C
8-halogenated alkoxy, C
1-C
8-alkyl alkylthio base, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl sulfanyl, C
2-C
8-alkene oxygen base, there is the C of 1 to 5 halogen atom
2-C
8-haloalkene oxygen base, C
3-C
8-alkynyloxy group, there is the C of 1 to 5 halogen atom
3-C
8-halo alkynyloxy group, C
3-C
8-cycloalkyl, there is the C of 1 to 5 halogen atom
3-C
8-halogenated cycloalkyl, C
1-C
8-alkyl-carbonyl, there is the C of 1 to 5 halogen atom
1-C
8-halogenated alkyl carbonyl, C
1-C
8-alkyl-carbamoyl, two-C
1-C
8-alkyl-carbamoyl, (N-C
1-C
8-alkyl) oxo (oxy) formamyl, C
1-C
8-alkoxy amino formyl radical, (N-C
1-C
8-alkyl)-C
1-C
8-alkoxy amino formyl radical, C
1-C
8-alkoxy carbonyl, there is the C of 1 to 5 halogen atom
1-C
8-halo alkoxy carbonyl, C
1-C
8-alkyl carbonyl oxy, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl carbonyl oxygen base, C
1-C
8-alkyl-carbonyl-amino, there is the C of 1 to 5 halogen atom
1-C
8-halogenated alkyl carbonyl amino, C
1-C
8-alkyl amino carbonyl oxy, two-C
1-C
8-alkyl amino carbonyl oxy, C
1-C
8-alkoxyl group carbonyl oxygen base, C
1-C
8-alkyl sulfenyl (sulphenyl), there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl sulfenyl, C
1-C
8-alkyl sulphinyl (sulphinyl), there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl sulfinyl, C
1-C
8-alkyl sulphonyl (sulphonyl), there is the C of 1 to 5 halogen atom
1-C
8-halogenated alkyl sulfonyl, (C
1-C
6-Alkoximino)-C
1-C
6-alkyl, (C
1-C
6-alkene oxygen base imino-)-C
1-C
6-alkyl, (C
1-C
6-alkynyloxy group imino-)-C
1-C
6-alkyl, (benzyloxy imino-)-C
1-C
6-alkyl, benzyloxy, dibenzylsulfide alkyl, benzylamino, phenoxy group, phenyl sulfanyl or phenyl amino;
Described method comprises:
(A)-according to the first step of reaction scheme 1:
scheme 1
Wherein :-X and p are as defined above;
-R is C
1-C
8-alkyl;
-Hal represents halogen atom
This step comprises:
A) 2-haloperidid derivative is 1-10, in polar solvent, under alkali exists, reacts in the mol ratio of 2-haloperidid derivative/alkyl cyanoacetates with alkyl cyanoacetates, and wherein the mol ratio of alkali/2-haloperidid derivative is 1-4;
B) then add acid, until the pH value of reaction mixture is 1-5;
Obtain 2-methyl cyanopyridine derivative;
(B)-according to the second step of reaction scheme 2:
scheme 2
Wherein :-X, p is as defined above;
-R
1represent C
1-C
6-alkyl;
-R
2represent halogen atom or-OCOAlk group;
-Alk represents C
1-C
6-alkyl;
Described step comprises that the 2-methyl cyanopyridine derivative obtaining in step 1 is at general formula R
1cOR
2acylating agent and catalyzer exist under, in solvent, carry out catalytic reduction reaction under the hydrogen pressure of 4-40 bar, obtain 2-ethylamino pyridinyl derivatives;
(C)-according to the 3rd step of reaction scheme 3:
scheme 3
Wherein :-X and p are as defined above;
-R
1represent C
1-C
6-alkyl;
Described step comprises to the acid that adds 1-20 molar equivalent in the 2-ethylamino pyridine derivate obtaining in step 2, is hydrolyzed to the temperature that reflux at 20 ℃, obtains the compound of general formula (I).
For the purposes of the present invention:
-halogen atom can be bromine atoms, chlorine atom, iodine atom or fluorine atom.Preferably, halogen atom refers to chlorine atom;
Refer to-C of-carboxyl (=O) OH;
-refer to-C of carbonyl (=O)-;
Refer to-C of-formamyl (=O) NH
2;
Refer to-C of-N-hydroxyl amino formyl radical (=O) NHOH;
-alkyl, thiazolinyl and alkynyl and the part that contains these terms can be straight or brancheds.
In the compound of preparation general formula of the present invention (I), prepare 2-methyl cyanopyridine derivative by 2-haloperidid derivative and only complete by a step.And the productive rate that 2-methyl cyanopyridine derivative is reduced to the reactions steps of 2-ethylamino pyridine derivate is 65% to 95%.Therefore, this method can be used in technical scale.
According to the present invention, 2-pyridyl can be by (X) in each position
preplace, wherein X and n are as defined above.Preferably, the present invention relates to the preparation of the 2-ethylamino pyridine derivate of general formula (I), wherein can select separately following different feature or select the combination of these features:
-about p, p is 1,2 or 3.More preferably, p is 2.
-about X, X independently selected from halogen atoms, C
1-C
8-alkyl or there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl.More preferably, X is independently selected from chlorine or CF
3;
-the position that replaced by X about 2-pyridyl, 2-pyridyl is replaced by X at 3-and/or 5-position.More preferably, 2-pyridyl is replaced by X at 3-and/or 5-position.
Method of the present invention is particularly useful for making:
The chloro-5-of-N-2-[3-(trifluoromethyl)-2-pyridyl] ethamine or
-N-2-[3,5-dichloro-2-pyridyl base] ethamine.
Comprise that according to the first step (steps A) of method of the present invention 2-haloperidid derivative is 1-10, in polar solvent, under alkali exists, reacts in the mol ratio of 2-haloperidid derivative/alkyl cyanoacetates with alkyl cyanoacetates, wherein the mol ratio of alkali/2-haloperidid derivative is 1-4; Then add acid, until the pH value of reaction mixture is 1-5; Obtain 2-methyl cyanopyridine derivative.Preferably, steps A can be carried out under the following conditions, and their combination can be selected separately or select to these conditions:
-polar solvent is selected from methyl-sulphoxide (DMSO), ether solvents, amide solvent or urea solvent.More preferably, solvent is selected from methyl-sulphoxide (DMSO), diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tert amyl methyl ether(TAME), two
alkane, tetrahydrofuran (THF) (THF), 1,2-glycol dimethyl ether, 1,2-diethoxyethane, phenylmethylether, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-methyl formyl aniline, N-Methyl pyrrolidone (NMP), hexamethyl-phosphorus-triamide or 1,3-dimethyl-2-2-imidazolone (DMA).More preferably, solvent is selected from tetrahydrofuran (THF) (THF), N-methyl-pyrrolidone (NMP), 1,3-dimethyl-2-2-imidazolone (DMA) or methyl-sulphoxide (DMSO);
The mol ratio of-2-haloperidid derivative/alkyl cyanoacetates is 1-5;
-alkyl cyanoacetates is selected from methyl-cyanacetate, ethyl cyanacetate or the cyanoacetic acid tert-butyl ester;
-alkali is selected from that alkaline earth metal alkali, alkalimetal hydride alkali, hydroxide bases, aminocompound alkali, alkoxide base, acetic acid are saline and alkaline, carbonate bases, hydrogen-carbonate are saline and alkaline or tertiary amine base.More preferably, it is saline and alkaline that described alkali is selected from hydrogen-carbonate, comprise sodium hydride, sodium amide, lithium diisopropylamine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium acetate, potassium acetate, lime acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, saleratus, sodium bicarbonate, volatile salt, Trimethylamine 99, triethylamine, Tributylamine, N, accelerine, N, N-dimethyl benzylamine pyridine, N-methyl piperidine, N-methyl-morpholine, N, N-dimethyl aminopyridine, diazabicyclooctane (DABCO), Diazabicyclononene (DBN) or diazabicylo undecylene (DBU).More preferably, described alkali is selected from potassium hydroxide, sodium hydroxide, saleratus, sodium bicarbonate or sodium hydride;
The mol ratio of-alkali/2-haloperidid derivative is 1-2.5;
-the acid that adds is mineral acid.Suitable mineral acid comprises HCl and H
2sO
4.More preferably, add HCl;
-add acid, until the pH value of reaction mixture is 2-4, more preferably 2.
Steps A not necessarily needs specific temperature condition.Preferably, steps A is carried out to the temperature refluxing at 0 ℃.More preferably, steps A is carried out at the temperature of 0 ℃ to 100 ℃.
Second step (step B) according to method of the present invention comprises that the 2-methyl cyanopyridine derivative obtaining in step 1 is at general formula R
1cOR
2acylating agent and catalyzer exist under, in solvent, carry out catalytic reduction reaction under the hydrogen pressure of 4-40 bar, obtain 2-ethylamino pyridinyl derivatives.Preferably, step B can carry out under the following conditions, and their combination can be selected separately or select to these conditions:
-catalyzer is metal catalyst.Suitable metal catalyst comprise nickel-, platinum-or palladium-catalyst based, such as Raney nickel (Raney nickel), rhodium/aluminum oxide, palladium/charcoal, palladium/calcium carbonate, palladium/silicon-dioxide, palladium hydroxide, platinum/charcoal or platinum/aluminum oxide.More preferably, use palladium/charcoal;
-solvent is organic acid, and more preferably, solvent is C
1-C
6-alkanoic acid or formic acid.Suitable C
1-C
6-alkanoic acid comprises acetic acid, propionic acid, butyric acid, valeric acid or caproic acid.More preferably, solvent is acetic acid;
-acylating agent is C
1-C
6-alkanoic acid anhydride or formic anhydride.Suitable C
1-C
6-alkanoic acid anhydride comprises diacetyl oxide, propionic anhydride, butyryl oxide, valeric anhydride or caproic anhydride.More preferably, acylating agent is diacetyl oxide;
-hydrogen pressure is 4-35 bar.
Step B not necessarily needs specific temperature condition.Preferably, step B carries out at the temperature of 16 ℃ to 70 ℃.More preferably, step B carries out at the temperature of 20 ℃ to 40 ℃.
Comprise to the acid that adds 1-20 molar equivalent in the 2-ethylamino pyridine derivate obtaining in step 2 according to the 3rd step (step C) of method of the present invention, be hydrolyzed to the temperature that reflux at 20 ℃, obtain the compound of general formula (I).Preferably, step C can carry out under the following conditions, and their combination can be selected separately or select to these conditions:
-the acid that adds is mineral acid.Suitable mineral acid comprises HCl, H
3pO
4, H
2sO
4, HBr, HI or HF.Preferably, acid is HCl or H
2sO
4.More preferably, acid is HCl;
The acid of-2-10 molar equivalent joins in the 2-ethylamino pyridine derivate obtaining in step 2 (step B).More preferably, the acid of 5 molar equivalents joins in the 2-ethylamino pyridine derivate obtaining in step 2 (step B);
-reaction is carried out under refluxing.
The compound of above-mentioned general formula (I) is the intermediate that can be used for preparing known agricultural chemical compound.These known agricultural chemical compounds can obtain by the compound of above-mentioned general formula (I) and the coupling of halogenation benzoyl derivative.Therefore, as mentioned above, the invention still further relates to a kind of method, comprise another step (D) according to reaction scheme 4:
scheme 4
Wherein :-X and p are as defined above;
-A represent phenyl or have one, two or three can be identical or different heteroatomic 5-, 6-or 7-unit non-condensed heterocycle, heterocycle can connect by a carbon atom; This group is optionally replaced independently selected from following substituting group by one or more: halogen atom, nitro, cyano group, hydroxyl, amino, sulfanyl, five fluoro-λ
6-sulfanyl, formyl radical, methanoyl, formamido group, carboxyl, C
1-C
8-alkyl, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
8-alkylamino, two-C
1-C
8-alkylamino, C
1-C
8-alkoxyl group, there is the C of 1 to 5 halogen atom
1-C
8-halogenated alkoxy, C
1-C
8-alkoxy-C
2-C
8-thiazolinyl, C
1-C
8-alkyl alkylthio base, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl sulfanyl, C
1-C
8-alkoxy carbonyl, there is the C of 1 to 5 halogen atom
1-C
8-halo alkoxy carbonyl, C
1-C
8-alkyl carbonyl oxy, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl carbonyl oxygen base, C
1-C
8-alkyl sulfenyl, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl sulfenyl, C
1-C
8-alkyl sulphinyl, there is the C of 1 to 5 halogen atom
1-C
8-haloalkyl sulfinyl, C
1-C
8-alkyl sulphonyl, there is the C of 1 to 5 halogen atom
1-C
8-halogenated alkyl sulfonyl or C
1-C
8-alkyl sulfonamide;
Described step comprises that the acyl halide derivative containing in the 2-ethylamino pyridine that obtains in the step 3 of aforesaid method and organic solvent, under alkali exists, linked reaction occurs, and obtains N-[2-(2-pyridyl) ethyl of general formula (II)] carboxamide derivative.
According to the present invention, A can represent five yuan of non-condensed heterocycles.The wherein A preparing according to the inventive method is the compound that the object lesson of the compound of five-membered ring comprises general formula (II), wherein:
*a represents the heterocycle of general formula (A-1)
In formula:
-R
3and R
4identical or different, can be hydrogen atom, halogen atom, amino, nitro, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
5can be halogen atom, nitro, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-2)
In formula:
-R
6can be hydrogen atom, halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
7and R
8can be identical or different, can be hydrogen atom, halogen atom, amino, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-3)
In formula:
-R
9can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
10can be hydrogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-4)
In formula:
-R
11and R
12can be identical or different, can be hydrogen atom, halogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkylthio, C
1-C
4-alkyl sulphonyl, optionally by halogen atom or C
1-C
4the phenyl that-alkyl replaces, or optionally by halogen atom or C
1-C
4the pyridyl that-alkyl replaces;
-R
13can be halogen atom, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl or there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy.
*a represents the heterocycle of general formula (A-5)
In formula:
-R
14and R
15can be identical or different, can be hydrogen atom, halogen atom, C
1-C
4-alkyl, C
1-C
4-alkoxyl group or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
16can be hydrogen atom, halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-6)
In formula:
-R
17can be hydrogen atom, halogen atom, cyano group, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
18and R
20can be identical or different, can be hydrogen atom, halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
19can be hydrogen atom, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxy-C
1-C
4-alkyl, hydroxyl-C
1-C
4-alkyl, C
1-C
4-alkyl sulphonyl, two (C
1-C
4-alkyl) amino-sulfonyl, C
1-C
6-alkyl-carbonyl, optionally by halogen atom or C
1-C
4the phenyl sulfonyl that-alkyl replaces, or optionally by halogen atom or C
1-C
4the benzoyl that-alkyl replaces.
*a represents the heterocycle of general formula (A-7)
In formula:
-R
21can be hydrogen atom, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxy-C
1-C
4-alkyl, hydroxyl-C
1-C
4-alkyl, C
1-C
4-alkyl sulphonyl, two (C
1-C
4-alkyl) amino-sulfonyl, C
1-C
6-alkyl-carbonyl, optionally by halogen atom or C
1-C
4the phenyl sulfonyl that-alkyl replaces, or optionally by halogen atom or C
1-C
4the benzoyl that-alkyl replaces;
-R
22, R
23and R
24can be identical or different, can be hydrogen atom, halogen atom, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl or C
1-C
4-alkyl-carbonyl.
*a represents the heterocycle of general formula (A-8)
In formula:
-R
25can be hydrogen atom or C
1-C
4-alkyl;
-R
26can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-9)
In formula:
-R
27can be hydrogen atom or C
1-C
4-alkyl;
-R
28can be halogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl or optionally by halogen atom or C
1-C
4the phenyl that-alkyl replaces.
*a represents the heterocycle of general formula (A-10)
In formula:
-R
29can be hydrogen atom, halogen atom, amino, cyano group, C
1-C
4-alkylamino, two-(C
1-C
4-alkyl) amino, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, or optionally by halogen atom or C
1-C
4the phenyl that-alkyl replaces;
-R
30can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-11)
In formula:
-R
31can be hydrogen atom, halogen atom, amino, cyano group, C
1-C
4-alkylamino, two-(C
1-C
4-alkyl) amino, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
32can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-12)
In formula:
-R
33can be halogen atom, cyano group, nitro, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
3-C
6-cycloalkyl, C
1-C
4-alkoxyl group, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio, aminocarboxyl or aminocarboxyl-C
1-C
4-alkyl;
-R
34can be hydrogen atom, halogen atom, cyano group, nitro, C
1-C
4-alkyl, C
1-C
4-alkoxyl group or C
1-C
4-alkylthio;
-R
35can be hydrogen atom, phenyl, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, hydroxyl-C
1-C
4-alkyl, C
2-C
6-thiazolinyl, C
3-C
6-cycloalkyl, C
1-C
4-alkylthio-C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio-C
1-C
4-alkyl, C
1-C
4-alkoxy-C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy-C
1-C
4-alkyl.
*a represents the heterocycle of general formula (A-13)
In formula:
-R
36can be hydrogen atom, halogen atom, cyano group, nitro, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
3-C
6-cycloalkyl, C
1-C
4-alkoxyl group, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio, aminocarboxyl or aminocarboxyl-C
1-C
4-alkyl;
-R
37can be hydrogen atom, halogen atom, cyano group, C
1-C
4-alkyl, C
1-C
4-alkoxyl group, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy or C
1-C
4-alkylthio;
-R
38can be hydrogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, hydroxyl-C
1-C
4-alkyl, C
2-C
6-thiazolinyl, C
3-C
6-cycloalkyl, C
1-C
4-alkylthio-C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio-C
1-C
4-alkyl, C
1-C
4-alkoxy-C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy-C
1-C
4-alkyl or optionally by halogen atom, C
1-C
4-alkyl, C
1-C
4the phenyl that-alkoxyalkyl or nitro replace.
*a represents the heterocycle of general formula (A-14)
In formula:
-R
39can be hydrogen atom, halogen atom, cyano group, nitro, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
3-C
6-cycloalkyl, C
1-C
4-alkoxyl group, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio, aminocarboxyl or aminocarboxyl-C
1-C
4-alkyl;
-R
40can be hydrogen atom, halogen atom, cyano group, C
1-C
4-alkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
41can be hydrogen atom, phenyl, benzyl, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, hydroxyl-C
1-C
4-alkyl, C
2-C
6-thiazolinyl, C
3-C
6-cycloalkyl, C
1-C
4-alkylthio-C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio-C
1-C
4-alkyl, C
1-C
4-alkoxy-C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy-C
1-C
4-alkyl.
*a represents the heterocycle of general formula (A-15)
In formula:
-R
42can be hydrogen atom, halogen atom, C-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
43can be halogen atom, C-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-16)
R in formula
44and R
45can be identical or different, can be hydrogen atom, halogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, optionally by halogen atom or C
1-C
4the phenyl that-alkyl replaces, or optionally by halogen atom or C
1-C
4the heterocyclic radical that-alkyl replaces.
*a represents the heterocycle of general formula (A-17)
In formula:
-R
46can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
47can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-18)
R in formula
48can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-19)
In formula:
-R
49can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
50can be hydrogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl or optionally by halogen atom or C
1-C
4the phenyl that-alkyl replaces.
*a represents the heterocycle of general formula (A-20)
R in formula
51can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
According to the present invention, A can also represent hexa-atomic non-condensed heterocycle.The wherein A preparing according to the inventive method is that the object lesson of the compound of hexa-member heterocycle comprises:
*a represents the heterocycle of general formula (A-21)
In formula:
-R
52can be halogen atom, hydroxyl, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio or there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy;
-R
53, R
54and R
55can be identical or different, can be hydrogen atom, halogen atom, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, C
1-C
4-alkyl sulphinyl or C
1-C
4-alkyl sulphonyl.
*a represents the heterocycle of general formula (A-22)
In formula:
-R
56can be hydrogen atom, halogen atom, hydroxyl, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxyl group, C
1-C
5-alkylthio, C
2-C
5-alkenylthio group, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, optionally by halogen atom or C
1-C
4the phenoxy group that-alkyl replaces, or optionally by halogen atom or C
1-C
4the thiophenyl that-alkyl replaces;
-R
57, R
58and R
59can be identical or different, can be hydrogen atom, halogen atom, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, C
1-C
4-alkyl sulphinyl, C
1-C
4-alkyl sulphonyl or optionally by halogen atom or C
1-C
4the N-morpholine that-alkyl replaces, or optionally by halogen atom or C
1-C
4the thienyl that-alkyl replaces.
*a represents the heterocycle of general formula (A-23)
R in formula
60, R
61, R
62and R
63can be identical or different, can be hydrogen atom, halogen atom, hydroxyl, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy, C
1-C
4-alkyl sulphinyl or C
1-C
4-alkyl sulphonyl.
*a represents the heterocycle of general formula (A-24)
In formula:
-R
64can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
65can be hydrogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
6-alkoxy carbonyl, the optionally benzyl, the optionally benzyloxycarbonyl or the heterocyclic radical that are replaced by 1 to 3 halogen atom that are replaced by 1 to 3 halogen atom.
*a represents the heterocycle of general formula (A-25)
In formula:
-R
66can be halogen atom, hydroxyl, cyano group, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl, C
1-C
4-alkoxyl group, C
1-C
4-alkylthio, there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkylthio or there is the C of 1 to 5 halogen atom
1-C
4-halogenated alkoxy;
-R
67can be hydrogen atom, C
1-C
4-alkyl, there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl or benzyl.
*a represents the heterocycle of general formula (A-26)
In formula:
-X
1can be sulphur atom ,-SO-,-SO
2-or-CH
2-;
-R
68can be C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
-R
69and R
70can be identical or different, can be hydrogen atom or C
1-C
4-alkyl.
*a represents the heterocycle of general formula (A-27)
In formula:
-R
71can be C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl;
*a represents the heterocycle of general formula (A-28)
In formula:
-R
72can be C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
*a represents the heterocycle of general formula (A-29)
R in formula
73can be halogen atom, C
1-C
4-alkyl or there is the C of 1 to 5 halogen atom
1-C
4-haloalkyl.
According to the present invention, A can also represent the optional phenyl replacing.Preferably, the present invention relates to N-[2-(2-pyridyl) ethyl of general formula (II)] preparation of carboxamide derivative, wherein A is phenyl, wherein can select separately following feature or select the combination of these features:
-A is replaced by 1 or 2 substituting groups.More preferably, A is replaced by 1 substituting group.
-each substituting group is independently selected from hydrogen atom, halogen atom, C
1-C
8alkyl or there is the C of 1 to 5 halogen atom
1-C
8haloalkyl.More preferably, each substituting group is independently selected from chlorine or CF
3;
-phenyl moiety is substituted at ortho position.
This method is particularly useful for making the compound of general formula (II):
The chloro-5-of-N-{2-[3-(trifluoromethyl)-2-pyridyl] ethyl }-2-trifluoromethyl benzamide;
The chloro-5-of-N-{2-[3-(trifluoromethyl)-2-pyridyl] ethyl }-2-phenyl-iodide methane amide; Or
-N-{2-[3,5-dichloro-2-pyridyl base] ethyl }-2-trifluoromethyl benzamide.
The 4th step (step D) according to method of the present invention comprises that the 2-ethylamino pyridine and the halogenation benzoyl derivative that in step C, obtain carry out linked reaction, obtain the compound of above-mentioned general formula (II).This linked reaction is undertaken by known method.For example, can be according to Schotten Ber.1884, this linked reaction is carried out in the Schotten-Baumann reaction of describing in 17,2544 and Baumann Ber.1886,19,3218, and the content of these documents is by reference to being incorporated into this.
Can prepare the compound of general formula of the present invention (I) and general formula (II) according to aforesaid method.It should be understood that, according to those skilled in the art's general knowledge and available public technology, those skilled in the art can adjust aforesaid method according to the special property of the synthetic each compound of need.
Some intermediate that can be used for the compound of preparing general formula (I) is novel.Therefore, the invention still further relates to the novel intermediate compound that can be used for the compound of preparing general formula (I).Therefore,, according to the present invention, provide the compound of a kind of general formula (III)
In formula:
-X and p are as defined above;
-R
1represent C
1-C
6-alkyl.
The present invention is described now with the following Examples.
the preparation of the chloro-5-of 3-(trifluoromethyl)-2-ethamine-pyridyl
the preparation of the chloro-5-of step 1:3-(trifluoromethyl)-2-methyl-cyanide yl pyridines
To being furnished with the nmp solution (14.6%w/v), the KOH (2.2 equivalent) that add the chloro-5-of 2,3-bis-(trifluoromethyl)-pyridine in two neck round-bottomed flasks of magnetic stir bar (magnetic bar), thermometer and reflux condensing tube.This solution is heated to 70 ℃, slowly adds ethyl cyanacetate (1.2 equivalent).After reinforced, by reaction medium heating 3 hours.Add 36% the HCl aqueous solution, making pH value is 2, by mixture 130 ℃ of heating 2 hours.At 20 ℃ of NaOH aqueous solution that add 1N, by methyl tertiary butyl ether (MTBE) aqueous phase extracted 3 times.Merge organic phase, wash with water, use MgSO
4dry, be concentrated into dry.Isolated yield is 94%.
NMR
1H(300Mz，CDCl
3)：4.15(s，2H，CH
2)，8.0(s，1H，Hpyr.)，8.79(s，1H，Hpyr.)。
the preparation of the chloro-5-of step 2:3-(trifluoromethyl)-2-ethyl acetamide-pyridyl
In hydrogenation reactor, add the chloro-5-trifluoromethyl-2-of 3-methyl-cyanide yl pyridines (7 grams, 31.4 mmoles), Pd/C 5% (1.05 grams), Ac
2o (12.8 grams, 125.8 mmoles, 4 equivalents), AcOH (60 milliliters).Material in reactor is stirred 5 hours at 20 ℃ under the hydrogen pressure of 30 bar.Except dehydrogenation, filter out catalyzer, solvent evaporation.Obtain 8.4 grams of rough required products.Productive rate=71% of HPLC titration.
Mass spectrum: 266DA, MH
+: 267
the preparation of the chloro-5-of step 3:3-(trifluoromethyl)-2-ethamine-pyridyl
Add the chloro-5-of above-mentioned rough 3-(trifluoromethyl)-2-ethyl acetamide-pyridyl (22.2 mmole), water (50 milliliters), HCl 37% (4.3 grams, 5 equivalents) to being furnished with in two neck round-bottomed flasks of magnetic stir bar, thermometer and reflux condensing tube.This solution refluxes 5 hours.Use CH
2cl
2(3 × 20 milliliters) at room temperature wash water 3 times.By HPLC titration water.In solution, the productive rate of titration is 92%.Mass spectroscopy: 224DA, MH
+225.
Under these conditions, the overall yield (step 2 and step 3) of being prepared 2-ethylamino pyridinyl derivatives by 2-methyl cyanopyridine derivative is 65%, and this is acceptable in technical scale.
Use the method disclosing in patent application WO 2004/016088 to carry out comparative example: to prepare the chloro-5-of 3-(trifluoromethyl)-2-ethamine-pyridyl according to the method disclosing in WO 2004/016088 by the chloro-5-of 3-(trifluoromethyl)-2-methyl-cyanide yl pyridines
In hydrogenation reactor, add the chloro-5-trifluoromethyl-2-of 3-methyl-cyanide yl pyridines (1.5 grams, 6.72 mmoles), Pd/C 5%, AcOH (7 milliliters).Material in reactor is stirred 15 hours at 20 ℃ under the hydrogen pressure of 6 bar.Remove hydrogen, filter out catalyzer, solvent evaporation.Obtain 1.4 grams of rough required products.The productive rate of HPLC titration is 19%.
Mass spectroscopy: 224DA, MH
+225.
Under these conditions, prepared the overall yield of 2-ethylamino pyridinyl derivatives only have 19% by 2-methyl cyanopyridine derivative, this is to accept in technical scale.
After above-mentioned steps 3, can carry out another step, prepare the known chloro-5-of mycocide N-{2-[3-(trifluoromethyl)-2-pyridyl] ethyl }-2-trifluoromethyl benzamide:
the chloro-5-of step 4:N-{2-[3-(trifluoromethyl)-2-pyridyl] ethyl } system of-2-trifluoromethyl benzamide
standby
Add the above-mentioned aqueous solution to being furnished with in two neck round-bottomed flasks of magnetic stir bar, thermometer and reflux condensing tube, add THF (80 milliliters) solution of 2-trifluoromethyl benzoyl chloride (1.2 equivalent), then add the NaOH aqueous solution of 2N, until pH value is 8.After 1 hour, use iPr
2o (40 milliliters) aqueous phase extracted, mixes organic phase, with the HCl aqueous solution (2 × 40 milliliters) and water (40 milliliters) washing of 1N.By HPLC titration organic phase.In solution, the productive rate of titration is 90%.
In organic solution, add heptane (70 milliliters), distillation THF and iPr
2o, obtains the precipitation of required compound.After filtration, with heptane/CH
2cl
2(90/10) washing leaching cake, dry.Isolated yield is 80%.
Claims (11)
1. the method for preparing the compound of general formula (II), is characterized in that, described method comprises according to the step of reaction scheme 4 (D):
scheme 4
Wherein :-p equals 1,2,3 or 4 integer;
-X is identical or different, and is halogen atom or the C with 1 to 5 halogen atom
1-C
8-haloalkyl;
-Hal represents halogen atom;
-A represents the phenyl being replaced independently selected from following substituting group by one or two: halogen atom or have the C of 1 to 5 halogen atom
1-C
8-haloalkyl;
Described step comprises, under existing, alkali be there is to linked reaction in the acyl halide derivative containing in the 2-of general formula (I) (amino-ethyl)-pyridine derivate and organic solvent, obtain N-[2-(pyridine-2-yl) ethyl of general formula (II)] carboxamide derivative
Wherein, 2-(amino-ethyl)-pyridine derivate or its salt of described general formula (I) are prepared by the following method:
(A)-according to the first step of reaction scheme 1:
scheme 1
Wherein :-X and p are as defined above;
-R is C
1-C
8-alkyl;
-Hal represents halogen atom;
This step comprises:
A) making 2-haloperidid derivative is reacting 1-10, in polar solvent, under alkali exists with alkyl cyanoacetates in the mol ratio of 2-haloperidid derivative/alkyl cyanoacetates, and wherein the mol ratio of alkali/2-haloperidid derivative is 1-4;
B) then add acid, until the pH value of reaction mixture is 1-5;
Obtain 2-(cyano methyl)-pyridine derivate;
(B)-according to the second step of reaction scheme 2:
scheme 2
Wherein :-X, p is as defined above;
-R
1represent C
1-C
6-alkyl;
-R
2represent halogen atom or-OCOAlk group;
-Alk represents C
1-C
6-alkyl;
Described step comprises makes 2-(the cyano methyl)-pyridine derivate obtaining in the first step at general formula R
1cOR
2acylating agent and catalyzer exist under, in solvent, carry out catalytic reduction reaction under the hydrogen pressure of 4-40 bar, obtain 2-(amino-ethyl)-pyridinyl derivatives, wherein said catalyzer be selected from nickel-, platinum-or palladium-catalyst based metal catalyst;
(C)-according to the 3rd step of reaction scheme 3:
scheme 3
Wherein :-X and p are as defined above;
-R
1represent C
1-C
6-alkyl;
Described step comprises to the acid that adds 1-20 molar equivalent in the aqueous solution of 2-(the amino-ethyl)-pyridine derivate obtaining in second step, is hydrolyzed to the temperature that reflux at 20 ℃, obtains the compound of general formula (I).
2. the method for claim 1, is characterized in that, p is 2.
3. the method for claim 1, is characterized in that, described catalyzer is Raney nickel, palladium/charcoal, palladium/calcium carbonate, palladium/silicon-dioxide, palladium hydroxide, platinum/charcoal or platinum/aluminum oxide.
4. the method as described in any one in claim 1-3, is characterized in that, X is selected from chlorine or CF independently of each other
3.
5. the method as described in any one in claim 1-3, is characterized in that, 2-pyridyl part in 3-position and/or 5-position replaced by X.
6. the method for claim 1, is characterized in that, the compound of general formula (I) is:
The chloro-5-of 2-[3-(trifluoromethyl)-pyridine-2-yl] ethamine, or
2-[3, the chloro-pyridine-2-of 5-bis-yl] ethamine.
7. the method as described in any one in claim 1-3, is characterized in that, step (A) is carried out to the temperature refluxing at 0 ℃.
8. the method as described in any one in claim 1-3, is characterized in that, step (B) is carried out at the temperature of 16 ℃ to 70 ℃.
9. the method as described in any one in claim 1-3, is characterized in that, each substituting group of A is selected from chlorine or CF independently of each other
3.
10. the method as described in any one in claim 1-3, is characterized in that, A is substituted at ortho position.
11. methods as described in any one in claim 1-3, is characterized in that, the compound of general formula (II) is:
The chloro-5-of N-{2-[3-(trifluoromethyl)-pyridine-2-yl] ethyl }-2-(trifluoromethyl) benzamide;
The chloro-5-of N-{2-[3-(trifluoromethyl)-pyridine-2-yl] ethyl }-2-phenyl-iodide methane amide; Or
N-{2-[3, the chloro-pyridine-2-of 5-bis-yl] ethyl }-2-(trifluoromethyl) benzamide.
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|---|---|---|---|
| EP04356202.4 | 2004-12-21 | ||
| EP04356202A EP1674455A1 (en) | 2004-12-21 | 2004-12-21 | Process for the preparation of a 2-ethylaminopyridine derivative |
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| EP3952548B1 (en) | 2008-08-08 | 2024-04-03 | Sun Patent Trust | Wireless communication base station device, wireless communication terminal device, and channel allocation method |
| CN103535353A (en) * | 2012-07-13 | 2014-01-29 | 陕西美邦农药有限公司 | Efficient bactericidal composition |
| CN103535362A (en) * | 2012-07-13 | 2014-01-29 | 陕西美邦农药有限公司 | Efficient bactericidal composition |
| CN103535355A (en) * | 2012-07-13 | 2014-01-29 | 陕西美邦农药有限公司 | Efficient bactericidal composition |
| CN103535354A (en) * | 2012-07-13 | 2014-01-29 | 陕西美邦农药有限公司 | Efficient bactericidal composition |
| UY35772A (en) | 2013-10-14 | 2015-05-29 | Bayer Cropscience Ag | NEW PESTICIDED COMPOUNDS |
| ES2665579T3 (en) * | 2013-11-15 | 2018-04-26 | Bayer Cropscience Aktiengesellschaft | Catalytic hydrogenation of nitriles |
| CN105237435B (en) * | 2015-09-21 | 2018-03-09 | 苏州大学 | A kind of preparation method of α cyano group amine |
| MX2019007640A (en) | 2016-12-21 | 2019-09-06 | Bayer Cropscience Ag | Catalytic hydrogenation of nitriles. |
| US10807955B2 (en) * | 2016-12-21 | 2020-10-20 | Bayer Cropscience Aktiengesellschaft | Process for the preparation of a 2-pyridylethylcarboxamide derivative |
| EP3826991A1 (en) * | 2018-07-26 | 2021-06-02 | Bayer Aktiengesellschaft | Crystalline form of fluopyram |
| CN109293565B (en) * | 2018-10-26 | 2021-08-06 | 江苏七洲绿色化工股份有限公司 | Preparation method of fluopyram |
| US11236070B2 (en) | 2019-05-16 | 2022-02-01 | Novartis Ag | Chemical process |
| CN110437139A (en) * | 2019-08-12 | 2019-11-12 | 大连九信精细化工有限公司 | A kind of synthetic method of fluopyram |
| CN111004170A (en) * | 2019-12-09 | 2020-04-14 | 西安近代化学研究所 | Continuous synthesis method of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine hydrochloride |
| CN111484448A (en) * | 2020-05-11 | 2020-08-04 | 中国农业科学院农业质量标准与检测技术研究所 | Fluopyram hapten, preparation method and application thereof, and antibody and method for detecting fluopyram |
| CN112552231B (en) * | 2020-12-11 | 2022-03-11 | 南京正荣医药化学有限公司 | Synthetic method of 2- (3-chloro-5- (trifluoromethyl) pyridine-2-yl) ethylamine |
| WO2022208370A1 (en) | 2021-03-31 | 2022-10-06 | Pi Industries Ltd. | Fused heterocyclic compounds and their use as pest control agents |
| CN115215793A (en) * | 2022-08-11 | 2022-10-21 | 南开大学 | Synthesis method of fluopyram |
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| US5364871A (en) * | 1989-09-15 | 1994-11-15 | Fujisawa Pharmaceutical Co., Ltd. | New thiazole derivatives, and pharmaceutical composition comprising the same |
| US5208247A (en) * | 1991-08-01 | 1993-05-04 | American Cyanamid Company | Pyridinium compounds which are useful as antagonists of platelet activating factor |
| IN191266B (en) * | 1999-09-16 | 2003-10-18 | Council Scient Ind Res | |
| JP2004517102A (en) * | 2001-03-30 | 2004-06-10 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | Method for producing amide from amine |
| SI1531673T1 (en) * | 2002-08-12 | 2006-06-30 | Bayer Cropscience Sa | Novel 2-pyridylethylbenzamide derivative |
| EP1449841A1 (en) * | 2003-02-19 | 2004-08-25 | Bayer CropScience SA | New fungicidal compounds |
| EP1500651A1 (en) * | 2003-07-25 | 2005-01-26 | Bayer CropScience S.A. | N-[2-(2-Pyridinyl)ethyl]benzamide compounds and their use as fungicides |
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| EP1674455A1 (en) | 2006-06-28 |
| JP2011207896A (en) | 2011-10-20 |
| DE602005025251D1 (en) | 2011-01-20 |
| IL183663A0 (en) | 2007-09-20 |
| EP1833793A1 (en) | 2007-09-19 |
| JP4794570B2 (en) | 2011-10-19 |
| JP2008524308A (en) | 2008-07-10 |
| CN101080390B (en) | 2011-07-27 |
| JP5526078B2 (en) | 2014-06-18 |
| TWI318624B (en) | 2009-12-21 |
| US7777045B2 (en) | 2010-08-17 |
| ATE490956T1 (en) | 2010-12-15 |
| EP1833793B1 (en) | 2010-12-08 |
| BRPI0516904B1 (en) | 2014-12-30 |
| CN102276520A (en) | 2011-12-14 |
| BRPI0516904A (en) | 2008-09-23 |
| US20080114176A1 (en) | 2008-05-15 |
| WO2006067106A1 (en) | 2006-06-29 |
| CN101080390A (en) | 2007-11-28 |
| IL183663A (en) | 2013-02-28 |
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